Of the rheumatic disorders which involve the diffuse connective tissue, scleroderma (systemic sclerosis) is characterized by fibrosis associated with distinctive lesions of the vascular and microvascular systems. Studies to define the vascular lesions in the applicants' laboratory have indentified an activity in serum which selectively kills endothelial cells in vitro. Loss of endothelial integrity with subsequent activation of platelet aggregation and plasma coagulation is proposed as the common denominator which activates smooth muscle cells to form the intimal proliferative lesion and which activates interstitial fibroblasts to produce the fibrotic lesion. Following preliminary evidence that monocyte activation produces soluble factors capable of endothelial cytotoxicity and fibroblast proliferation, a systematic study of the pathogenesis of scleroderma will be undertaken with the hypothesis: monocyte activation greater than endothelial injury greater than smooth muscle cell activation greater than intimal proliferative lesion leading to visceral insufficiency greather than fibroblast activation leading to fibrotic replacement of the interstitium with microvascular insufficiency. If confirmed, this novel hypothesis of scleroderma suggests several new approaches to therapeutic intervention.